Positive-Strand RNA Viral RdRps: From Structure Conservation and Activity Assay to Drug Development

Figures

• 

  Figure 1. Linear and spatial structures of the RdRps in four representative viruses. The seven motifs 3.6.(A–G) in the RdRp active region of SARS-CoV-2, DENV, HCV and CHIKV are sequentially consistent, and the overall spatial conformations of the enzyme molecules formed are similar. The linear and spatial structures of the RdRps were shown and analyzed using PyMOL-3.1.6.1 software. All the primary structure data were derived from the PDB database, respectively SARS-CoV-2 nsp12 (PDB, 7BW4), DENV NS5 (PDB, 4V0Q), HCV NS5B (PDB, 3FQK) and CHIKV nsP4 (PDB, 7Y38).

• 

  Figure 2. Protein-primed initiation and de novo initiation. Schematic description of RNA de novo mechanism and primer extension synthesis. (A) Protein-primed initiation uses a viral protein hydroxyl as primer. (B) De novo initiation synthesizes nascent RNA without a primer. (C) Copy-back mechanism generates a copy-back defective viral genome via RdRp template switching.

• 

  Figure 3. Programmed ribosome frameshift in SARS-CoV-2 genome. The slippery sequence “UUUAAAC” is located at nucleotides 21 to 27 after the nsp10 gene in the SARS-CoV-2 genome. Only when −1 PRF occurs can we translate the entire polyprotein 1ab, which contains nsp12 (RdRp) and downstream non-structural proteins. The slippery sequence was translated into partial amino acids of RdRp, without nsp11 production.

• 

  Figure 4. Molecular structure of RdRp inhibitors. The Molecular structure of six RdRp inhibitors, including Remdesivir, Sofosbuvir, Ribavirin, Favipiravir, Molnupiravir, and Dasabuvir.